RU2537847C2 - Novel fumarate salts of h3 histamine receptor antagonists - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to fumarate salts of 2-(cyclohexylmethyl)- N-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulphonamide, to based on them pharmaceutical compositions, method of their obtaining and methods of their application.

EFFECT: obtained are novel salts of 2-(cyclohexylmethyl)- N-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulphonamide, possessing properties of H3 histamine receptor antagonists.

16 cl, 9 dwg, 8 tbl, 6 ex

Description

FIELD OF THE INVENTION

The present invention relates to new forms of the fumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and their pharmaceutical compositions. The present invention also relates to methods for producing such salt forms and pharmaceutical compositions and methods for their use for the prevention and treatment of diseases associated with histamine H3 receptors.

BACKGROUND OF THE INVENTION

H3 histamine receptors are located in the central and peripheral nervous systems. The administration of histamine H3 receptor ligands can affect histamine levels or the secretion of neurotransmitters in the brain and periphery, and thus may be useful in treating certain disorders, including Alzheimer's disease and other dementias, obesity, central nervous system disorders such as insomnia and sleep disorders, narcolepsy, Parkinson's disease, attention deficit hyperactivity disorder, memory and learning disorders, epilepsy, schizophrenia, mild cognitive impairment, depression, revozhnost, cardiovascular disorders and gastrointestinal disorders.

To illustrate, a number of studies in the literature have shown cognitive enhancing properties of histamine H3 receptor antagonists in rodent models ( see, for example, Giovannini et al., Behav. Brain Res., 104, 147-155 (1999)). These reports suggest that antagonists and / or inverse agonists can be used to treat cognitive impairment in neurological diseases such as Alzheimer's disease and related neurodegenerative disorders. Alzheimer's disease is the most common cause of dementia in the elderly, and it is often characterized by one or more symptoms, such as memory loss, confusion, irritability and aggressiveness, sudden mood swings, speech impairment, prolonged memory loss, patient withdrawal, and loss of motor control.

2- (Cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide having the structure of Formula (I):

(I)

is a potent antagonist of the histamine H3 receptor with the properties of an inverse agonist. The preparation, physical properties and beneficial pharmacological properties of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide are described for example, in WO2005 / 118547 (also in US2007 / 0105834). WO2005 / 118547 describes 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide in the form of a free base , which is a viscous oil, or in the form of an oxalate salt having low crystallinity and thermal stability.

Although it is known that the preparation of salt forms can improve the physical or pharmaceutical properties of a pharmaceutically active compound, it is not possible to predict which salt forms may have advantages for a particular purpose until the actual production and characterization of the salt form. In particular, such advantages, without limitation, may include physical forms of the salt which provide better workability, solubility, or storage stability, for example. Other benefits may also include biological properties, such as improved bioavailability, reduced adverse reactions in the gastrointestinal tract (e.g., gastrointestinal irritation, partial breakdown of the compound, etc.) or better drug delivery to the intended target site. among other benefits.

The present invention therefore relates to the fumarate salts of 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, exhibiting improved properties that distinguish fumarate salts from the basic form 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7- sulfonamide per se, as well as from other salt forms of 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide known from the prior art.

In addition, the crystallinity and stability profile of the 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate salt makes this solid form unexpected and especially useful as a medicine.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to the fumarate salts of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide. The present invention also relates to new crystalline forms of the fumarate salts of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7- sulfonamide.

One aspect of the present invention is the 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide dihydrate monohydrate salt ( called "difumarate monohydrate salt") represented by Formula (II):

(II).

(Ii)

Another aspect of the present invention is difumaratnaya salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide ( named "difumarate salt") represented by Formula (III):

(III).

(III).

Another aspect of the present invention is the monofumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide ( named "monofumarate salt") represented by Formula (IV):

(IV).

(Iv).

Another aspect of the present invention is the hemifumarate dihydrate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (called "hemifumarate dihydrate salt") represented by Formula (V):

(V).

(V).

Another other aspect of the present invention is the hemifumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide (called "hemifumarate salt") represented by Formula (VI):

(VI).

(Vi).

Another aspect of the present invention is a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier.

Another other aspect of the present invention is a pharmaceutical composition obtained by formulating one or more compounds of the present invention with one or more pharmaceutically acceptable carriers.

Another aspect of the present invention is a process for preparing pharmaceutical compositions of 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide comprising formulating one or more compounds of the present invention with one or more pharmaceutically acceptable diluents.

Another other aspect of the present invention is a method of treating a pathology in which an H3 histamine receptor antagonist provides a therapeutic advantage.

The present invention is more fully discussed using the following drawings and a detailed description below.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

In Figure 1 X-ray powder diffraction pattern of crystalline 2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate of the present invention.

Figure 2 shows the infrared Fourier transform spectrum of (FTIR) 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline -7-sulfonamide difumarate monohydrate of the present invention.

Figure 3 presents a thermogram of differential scanning calorimetry - thermal gravimetric analysis and mass spectrometry (DSC-TGA-MS) 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of the present invention.

The Figure 4 presents an x-ray powder diffraction pattern of crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate of the present invention.

The Figure 5 presents an x-ray powder diffraction pattern of crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate of the present invention.

The Figure 6 presents the combination of thermograms DSC-TGA 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate and 2- (cyclohexylmethyl ) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide hemifumarate dihydrate of the present invention.

The Figure 7 presents the combination of x-ray powder diffraction patterns of crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate and crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate of the present invention.

The Figure 8 presents the sorption profile of the dynamic sorption of vapor (DVS) of water 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline -7-sulfonamide difumarate and the corresponding 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of the present invention.

Figure 9 shows the DVS hydroscopic profile of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate and the corresponding 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and abbreviations

The following abbreviations used above and throughout the description of the present invention, unless otherwise indicated, should be understood as having the following meanings:

DMF N, N- Dimethylformamide

ETOH ethanol

g gram

HPLC high performance liquid chromatography

mg milligram

ml milliliter

μl microliter

MTBE tert-butyl methyl ether

NMR nuclear magnetic resonance

RH relative humidity

Used above and throughout the description of the present invention, various expressions should have generally accepted meanings in the art. More specifically, the following expressions, unless otherwise indicated, should generally be understood as having the following meanings.

The term "difumarate monohydrate salt", as used herein, is intended to describe the difumarate monohydrate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2 , 3,4-tetrahydroisoquinoline-7-sulfonamide, which can be characterized using distinctive data as described herein. Characteristic data can be found in Figures 1, 2, 3, and 8. Difumarate monohydrate salt 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3 , 4-tetrahydroisoquinolin-7-sulfonamide is also synonymous with 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7 -sulfonamide difumarate hydrate and 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.

The term "difumarate salt", as used herein, is intended to describe the difumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3 , 4-tetrahydroisoquinoline-7-sulfonamide, which can be characterized using distinctive data as described herein. Characteristic data can be found in Figures 4 and 8. The difumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide is also synonymous with 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate, anhydrous 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and anhydride difumarate difumara anhydride.

The term “monofumarate salt”, as used herein, is intended to describe the monofumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3 , 4-tetrahydroisoquinoline-7-sulfonamide, which can be characterized using distinctive data as described herein. Characteristic data can be found in Figures 5 and 6. Monofumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide is also synonymously called 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate.

The term “hemifumarate salt”, as used herein, is intended to describe the hemifumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3 , 4-tetrahydroisoquinoline-7-sulfonamide, which can be characterized using distinctive data as described herein. Characteristic data can be found in Figures 6, 7 and 9. Hemifumarate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4- tetrahydroisoquinolin-7-sulfonamide is also synonymously referred to as 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide hemifumarate , 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dehydrate, anhydrous 2- (cyclohexylmethyl ) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate gemifumaratnaya anhydride salt.

The term “hemifumarate dihydrate salt”, as used herein, is intended to describe the hemifumarate dihydrate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2 , 3,4-tetrahydroisoquinoline-7-sulfonamide, which can be characterized using distinctive data as described herein. Characteristic data can be found in Figures 6, 7 and 9. Hemifumarate dihydrate salt of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4 Tetrahydroisoquinolin-7-sulfonamide is also synonymously called 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate.

The term "compounds of the present invention", as used herein, is intended to describe 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3, 4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7- difumarate sulfonamide, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2- (cyclohexylmethyl ) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfone hemifumarate amide and 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate.

The term “treatment” or “therapy” means alleviating or partially alleviating the symptoms, eliminating the causation of the symptoms either temporarily or permanently, or slowing down the symptoms of the disorder or condition. The compounds and compositions of the present invention are useful in the treatment of a pathology in which the histamine H3 receptor antagonist provides therapeutic utility. For example, treatment for Alzheimer's disease may include reversible disease progression, improved memory and / or cognition; and slowing down memory loss and / or cognition.

The term "patient" includes both humans and other mammals.

The term "pharmaceutically effective amount" is intended to describe the amount of a compound, composition, drug or other active ingredient effective in obtaining the desired therapeutic effect.

The present invention relates to a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of the formula ( II), wherein said method comprises the steps of contacting at elevated temperature or at ambient temperature 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1 , 2,3,4-tetrahydroisoquinoline-7-sulfonamide, dissolved in a suitable solvent or mixture of solvents, with fumaric acid, optionally dissolved in a solvent le or solvent mixture, and the precipitated solid is isolated, e.g., by filtration or solvent removal. In one embodiment, approximately two moles of fumaric acid reacts with the mole 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7 -sulfonamide. In another embodiment, more than two moles of fumaric acid reacts with the mole 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7 -sulfonamide.

Suitable solvents for dissolving 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide to effect salt formation include alcohols for example methanol, ethanol, 1- or 2-propanol, butanol isomeric alcohols, pentanol isomeric alcohols and hexanol isomeric alcohols, such as 2-methyl-4-pentanol; ketones such as acetone; esters, for example tetrahydrofuran and dioxane; acetic acid esters, for example ethyl acetate; organic acids, for example acetic acid; amides, for example N-methylpyrrolidinone, and nitriles, for example acetonitrile; and mixtures thereof, including mixtures containing water.

Also provided is a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, comprising into contact of 2- (cyclohexylmethyl) - N - {2- [2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate with water.

Another aspect of the present invention is a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate including exposure to 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate relative humidity above approximately 10% at ambient temperature, where the ambient temperature is in the range of 20 to 25 ° C.

A particular aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in crystalline form. The crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, which is described in the present the description is called Form I 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate. In one aspect of the present invention, the crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate characterized by an X-ray diffraction pattern containing peaks at approximately 5.31, 5.84, 7.00 and 8.67 degrees 2-theta.

Another particular aspect of the present invention is a process for preparing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in crystalline form.

To obtain 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in crystalline form 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide is dissolved in a suitable solvent or mixture of solvents, including without limitation methanol, ethanol, isopropanol, acetonitrile, acetone and water with fumaric acid, optionally dissolved in a solvent or in a mixture of solvents, and precipitated solid, for example, by filtering or removing the solvent by vacuum drying. In one embodiment, 1 mole of fumaric acid is reacted with a mole of 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7- sulfonamide. In another embodiment, two moles of fumaric acid is reacted with a mole 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7- sulfonamide.

For better crystallization control, it is possible to provide a crystallization initiation step, which is performed by seeding the reaction medium with a small amount of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2, 3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, previously obtained in crystalline form, for example, as described above. For such a seed, for example, the mass percentage of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7 sulfonamide difumarate monohydrate from 0.05% to 5% relative to the total amount of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4 Tetrahydroisoquinoline-7-sulfonamide in the basic form to be reacted. For example, can be used approximately 0.1% of the mass. 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate relative to the total amount of 2- (cyclohexylmethyl ) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide in the basic form to be reacted.

Another aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate. This difumarate salt is particularly suitable for the preparation of the difumarate monohydrate salt.

A particular aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate in crystalline form . The crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate described in the present description, is called Form I 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate. In one aspect of the present invention, the crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate characterized X-ray diffraction pattern including peaks at approximately 5.21, 5.67, 7.06 and 11.34 degrees 2-theta.

The present invention also relates to a process for the preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate, including dehydration of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.

In one aspect of the present invention, a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate includes exposure to 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate of low relative humidity, for example humidity below about 10% for two or more hours at ambient temperature, where the ambient temperature is in the range of 20 to 25 ° C.

In another aspect of the present invention, a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate includes heating 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate to a temperature above about 75 ° C.

In another aspect of the present invention, a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate includes heating 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate to a temperature above room temperature, for example above about 40 ° C, at low relative humidity, for example, humidity below about 10%.

Another aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate. A particular aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate in crystalline form . The crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate described in the present description, is called Form I 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate. In one aspect of the present invention, the crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate is characterized X-ray diffraction pattern, including peaks at approximately 3.37, 6.70, 13.36, 14.83, 15.88 and 17.65 degrees 2-theta.

The present invention also provides a process for the preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, comprising contacting at elevated temperature or at ambient temperature 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7- sulfonamide dissolved in a suitable solvent or mixture of solvents, with one equivalent of fumaric acid, optionally dissolved in a solvent or in a mixture of solvents, isolation of the precipitated solid difumarate monohydrate, e.g., by filtration or precipitation solvent. Monofumarate salt can be obtained after sequential crystallization of the mother liquor.

Suitable solvents for dissolving 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide to effect the formation of a monofumarate salt contain alcohols, for example methanol, ethanol, 1- or 2-propanol, butanol isomeric alcohols, pentanol isomeric alcohols and hexanol isomeric alcohols, such as 2-methyl-4-pentanol; ketones such as acetone; esters, for example tetrahydrofuran and dioxane; acetic acid esters, for example ethyl acetate; organic acids, for example acetic acid; amides, for example N-methylpyrrolidinone, and nitriles, for example acetonitrile; and mixtures thereof, including mixtures containing water.

Another aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate. A specific aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate in crystalline form . The crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate described in the present description, is called Form I 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate. In one aspect of the present invention, the crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate is characterized X-ray diffraction pattern including peaks at approximately 3.61, 7.22, 7.96, 8.21, 9.01, 10.82 and 15.66 degrees 2-theta.

The present invention also provides a process for the preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate, comprising stages at which 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4- is brought into contact at elevated temperature or at ambient temperature tetrahydroisoquinoline-7-sulfonamide, dissolved in a suitable solvent or mixture of solvents, with fumaric acid, optionally dissolved in a solvent or mixture of solvents, and pour precipitated solid, for example, by filtration or removal of solvent, and drying. Hemifumarate salt can be obtained after successive crystallization of their mother liquor.

Suitable solvents for dissolving 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide for the formation of hemifumarate salt contain alcohols, for example methanol, ethanol, 1- or 2-propanol, butanol isomeric alcohols, pentanol isomeric alcohols and hexanol isomeric alcohols, such as 2-methyl-4-pentanol; ketones such as acetone; esters, for example tetrahydrofuran and dioxane; acetic acid esters, for example ethyl acetate; organic acids, for example acetic acid; amides, for example N-methylpyrrolidinone, and nitriles, for example acetonitrile; and mixtures thereof, including mixtures containing water.

The present invention also provides a process for the preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate, comprising dehydration of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi fumarate dihydrate.

In one aspect of the present invention, a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate includes exposure to 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate of low relative humidity, for example humidity below about 10% for two or more hours.

In another aspect of the present invention, a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate includes heating 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi fumarate dihydrate above ambient temperature, where ambient temperature ranges from about 20 to about 25 ° C.

In another aspect of the present invention, a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate includes heating 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi-fumarate dihydrate above room temperature, for example above approximately 40 ° C, at low relative humidity, for example at a humidity below about 19%.

Another aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate. A specific aspect of the present invention is 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate in crystalline form. The crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi-fumarate dihydrate described in the present description is called Form I 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi-fumarate dihydrate. In one aspect of the present invention, the crystalline form of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate characterized by X-ray diffraction, including peaks at approximately 3.49, 6.93, 8.46, 10.34, 13.25, 13.75 and 15.40 degrees 2-theta.

The present invention also provides a process for the preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi fumarate dihydrate, including contacting 2- (cyclohexylmethyl) - N - {2- [2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate with water.

Another aspect of the present invention is a method for producing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi fumarate dihydrate , including exposure to 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate relative humidity above approximately 20% at ambient temperature, where the ambient temperature is in the range of 20 to 25 ° C.

The present invention provides pharmaceutical compositions comprising a 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in combination with a pharmaceutically acceptable carrier. In one aspect of the present invention, the pharmaceutical composition comprises crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate in combination with a pharmaceutically acceptable carrier.

The present invention also relates to pharmaceutical compositions containing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate in combination with a pharmaceutically acceptable carrier. In one aspect of the present invention, the pharmaceutical composition comprises crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate in combination with a pharmaceutically acceptable carrier.

The present invention also provides pharmaceutical compositions containing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate in combination with a pharmaceutically acceptable carrier. In one aspect of the present invention, the pharmaceutical composition comprises crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate in combination with a pharmaceutically acceptable carrier.

The present invention also provides pharmaceutical compositions containing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate in combination with a pharmaceutically acceptable carrier. In one aspect of the present invention, the pharmaceutical composition comprises crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate in combination with a pharmaceutically acceptable carrier.

The present invention also provides pharmaceutical compositions containing 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate in combination with a pharmaceutically acceptable carrier. In one aspect of the present invention, the pharmaceutical composition comprises crystalline 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate in combination with a pharmaceutically acceptable carrier.

Another aspect of the present invention is a pharmaceutical composition prepared by formulating a difumarate monohydrate salt with one or more pharmaceutically acceptable carriers.

Another aspect of the present invention is a pharmaceutical composition obtained by formulating a difumarate salt with one or more pharmaceutically acceptable carriers.

Another aspect of the present invention is a pharmaceutical composition prepared by formulating a monofumarate salt with one or more pharmaceutically acceptable carriers.

Another aspect of the present invention is a pharmaceutical composition prepared by formulating a hemifumarate salt with one or more pharmaceutically acceptable carriers.

Another aspect of the present invention is a pharmaceutical composition prepared by formulating a hemifumarate dihydrate salt with one or more pharmaceutically acceptable carriers.

The present invention also provides a method for preparing a pharmaceutical composition comprising formulating a difumarate monohydrate salt with one or more pharmaceutically acceptable diluents.

The present invention also provides a method for preparing a pharmaceutical composition comprising formulating a difumarate salt with one or more pharmaceutically acceptable diluents.

The present invention also provides a method for preparing a pharmaceutical composition comprising formulating a monofumarate salt with one or more pharmaceutically acceptable diluents.

The present invention also provides a method for preparing a pharmaceutical composition comprising formulating a hemifumarate salt with one or more pharmaceutically acceptable diluents.

The present invention also provides a method for preparing a pharmaceutical composition comprising formulating a hemifumarate dihydrate salt with one or more pharmaceutically acceptable diluents.

The compounds of the present invention can be administered in pharmaceutically acceptable dosage forms to a human patient and other mammals by local or systemic administration, including oral, inhalation, rectal, nasal, buccal, sublingual, vaginal, via the large intestine, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It should be understood that the specific route of administration may vary depending, for example, on the physiological state of the recipient.

The term "pharmaceutically acceptable dosage forms" refers to dosage forms of the compounds of the present invention and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, aerosols, inhalation tablets, lozenges, emulsions, solutions, granules, capsules and suppositories, as well as liquid injectable preparations, including liposome preparations. Methods and formulations are typically found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.

A particular aspect of the present invention relates to the compounds of the present invention to be administered in the form of a pharmaceutical composition.

Pharmaceutically acceptable carriers include at least one component selected from the group consisting of pharmaceutically acceptable carriers, diluents, coatings, excipients, excipients or media such as preservatives, excipients, disintegration enhancers, wetting agents, emulsifying agents, stabilizing agents , suspending agents, isotonic agents, sweeteners, flavoring agents, flavoring agents, coloring agents, antibacterial agents, antifungals formulations, other therapeutic agents, lubricants, agents for slowing down or providing adsorption and dispersing agents, depending on the nature of the route of administration and dosage forms.

Typical suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth or mixtures thereof.

Typical antibacterial and antifungal agents for preventing the action of microorganisms include parabens, chlorobutanol, phenol, sorbic acid, and the like.

Typical isotonic agents include sugars, sodium chloride, and the like.

Typical absorption retardants for prolonging absorption include aluminum monostearate and gelatin.

Typical adsorption aids to enhance absorption include dimethyl sulfoxide and related analogues.

Typical diluents, solvents, media, solubilizing agents, stabilizing agents, emulsifiers and emulsion stabilizers include water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1,3-propylene glycol, , glycerin, polyethylene glycols, dimethylformamide, Tween® 60, Span® 60, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate, fatty acid esters of sorbitan, vegetable oils (such as cottonseed oil, peanut oil, olive oil, castor oil and sesame oil) and injectable organic esters such as ethyl oleate and the like, or suitable mixtures of these substances.

Typical excipients include lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.

Typical disintegrants include starch, alginic acids, and certain complex silicates.

Typical lubricants include magnesium stearate, sodium lauryl sulfate, talc, as well as high molecular weight polyethylene glycols.

Pharmaceutical compositions of the present invention suitable for oral administration may be provided in discrete units, such as a solid dosage form, such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, or in the form of a powder or granules; in the form of a liquid dosage form, such as a solution or suspension in an aqueous liquid or in a non-aqueous liquid, or in the form of an oil-in-water liquid emulsion or a water-in-oil emulsion. The active ingredient may also be provided as a bolus, electuary or paste.

The term “solid dosage form” means a dosage form of a compound of the present invention in solid form, for example, capsules, tablets, pills, powders, dragees, or granules. In such solid dosage forms, the compound of the present invention is mixed with at least one inert traditional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) excipients or extenders, such as, for example, starches, lactose, sucrose , glucose, mannitol and silicic acid, (b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum, (c) humectants, such as, for example, glycerin, (d) agents to improve the disintegration, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) dissolution inhibitors, such as, for example, paraffin, (f) absorption accelerators, such as for example, quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, such as, for example, kaolin and bentonite, (i) lubricating agents, such as, for example, talc Calcium Stearate, Ma Stearate Nia, solid polyethylene glycols, sodium lauryl sulfate, (j) opacifying agents, (k) buffering agents, and agents which release the compound of the present invention in a certain part of the intestine with a delay.

A tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable setting, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used. A mixture of powdered compounds moistened with an inert liquid diluent may be molded in a suitable device to form molded tablets. Tablets may be optionally coated or grooved and may be formulated to provide a slow or controlled release of their active ingredient.

Solid compositions can also be used as fillers in soft and hard filled gelatin capsules using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

If necessary and for more efficient distribution, the compound may be microencapsulated or fixed in slow release delivery or targeted delivery systems, such as biocompatible, biodegradable polymer matrices (e.g. poly (d, l-lactide co-glycolide)), liposomes and microspheres , and subcutaneously or intramuscularly administered using a technique called a subcutaneous or intramuscular depot, to provide continuous, slow release of compound (s) over a 2-week period or longer. The compound can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or in some other sterile injectable medium immediately before use.

The term "liquid dosage form" means a dose of the active compound to be administered to a patient in liquid form, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as solvents, solubilizing agents and emulsifiers.

When aqueous suspensions are used, they may contain emulsifying agents or agents that promote the suspension.

Pharmaceutical compositions suitable for topical administration mean formulations that are in a form suitable for topical administration to a patient. The composition can be presented in the form of topically applied ointments, balms, powders, aerosols and agents used for inhalation, gels (based on water or alcohol), creams commonly known in the art, or included in a matrix base for application in a patch, which would allow controlled release of the compound across the transdermal barrier. When formulated as an ointment, the active ingredients can be applied either on a paraffin or water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream with a cream base oil-in-water. Formulations suitable for topical administration to the eye include eye drops, where the active ingredient is dissolved or suspended in a suitable vehicle, especially an aqueous solvent for the active ingredient. Formulations suitable for topical administration to the mouth include lozenges containing the active ingredient on a palatable basis, usually sucrose and arabian gum or tragacanth; lozenges containing the active ingredient in an inert basis, such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing the active ingredient in a suitable liquid carrier.

The oil phase of the emulsion of the pharmaceutical composition may consist of known ingredients in a known manner. While the phase may contain only an emulsifier (otherwise known as an emulsifying agent), it desirably contains a mixture of at least one emulsifier with fat or oil, or with fat and oil. In a specific embodiment, the hydrophilic emulsifier is included with the lipophilic emulsifier, which acts as a stabilizer. Together, emulsifier (s) with or without stabilizer (s) make up an emulsifying wax, and together with oil and fat make up the emulsifying base of the ointment, which forms the oil dispersion phase of the cream formulations.

If necessary, the aqueous phase of the cream base may include, for example, at least 30% w / w. polyhydric alcohol, i.e. an alcohol with two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerin and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected areas.

The selection of suitable oils or fats for the composition is based on achieving the desired properties. Thus, the cream, in particular, should be a non-greasy, non-staining and rinse-off product with a suitable consistency to avoid leakage from tubes or other containers. Branched or branched chain mono- or dibasic alkyl esters such as diisopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a mixture of branched chain esters known as Crodamol CAP can be used. They can be used individually or in combination depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

Pharmaceutical compositions suitable for rectal or vaginal administration mean compositions that are in a form suitable for rectal or vaginal administration to a patient and containing at least one compound of the present invention. Suppositories are a particular form for such formulations which can be obtained by mixing the compounds of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or wax for suppositories, which are solid at ambient temperature and liquid at body temperature, therefore melting in direct gut or vaginal cavity and release the active ingredient.

Injectable pharmaceutical compositions may be administered by intramuscular, intravenous, intraperitoneal and / or subcutaneous injection. The compositions of the present invention can be formulated in liquid solutions, in particular in physiologically compatible buffers, such as Hanks solution or Ringer's solution. In addition, the compositions can be formulated in solid form and re-dissolved or suspended immediately before use. Lyophilized forms are also included. The compositions are sterile and include emulsions, suspensions, aqueous and non-aqueous solutions for injection, which may contain suspending agents, thickeners and antioxidants, buffers, bacteriostatic factors and solutions that make the composition isotonic and have a suitable adjusted pH, with the blood of the intended recipient.

Pharmaceutical compositions of the present invention suitable for nasal or inhalation administration are in a form suitable for nasal or inhalation administration to a patient. The composition may contain a carrier in the form of a powder having a particle size, for example, in the range of 1 to 500 microns (including particles, size in the range of 20 to 500 microns, in increments of 5 microns, for example 30 microns, 35 microns, etc.) . Suitable compositions, wherein the carrier is a liquid, for administration as, for example, a nasal aerosol or as nasal drops, include aqueous or oily solutions of the active ingredient. Compositions suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. The inhaled therapeutic agent is readily administered by metered dose inhalers or any suitable dry powder inhaler.

The exact dosage levels of the active ingredient (s) in the compositions of the present invention can be varied to obtain the amount of active (s) ingredient (s) that is (e) effective to obtain the desired therapeutic response for a particular composition and route of administration for a patient. The dosage levels chosen for a particular patient, therefore, depend on a number of factors, including the desired therapeutic effect, route of administration, desired duration of treatment, etiology and severity of the disease, patient condition, weight, gender, nutrition and age, type and strength of each active ingredient, absorption rate, metabolism and / or excretion and other factors.

The total daily dose of a compound of the present invention administered to a patient in single or divided doses may be in amounts, for example, from about 0.001 to about 100 mg / kg body weight per day, and in particular from 0.01 to 10 mg / kg / day. For example, for adults, doses are usually from about 0.01 to about 100, in particular from about 0.01 to about 10 mg / kg of body weight per day by inhalation, from about 0.01 to about 100, in particular from about 0 , 1 to 70, more specifically from 0.5 to 10 mg / kg of body weight per day by oral administration and from about 0.01 to about 50, in particular from 0.01 to 10 mg / kg of body weight per day by intravenous introduction. The percentage of active ingredient in the composition may vary, although it must be in proportion to obtain a suitable dosage. Unit dosage formulations may contain such amounts of their fractional units as may be used to formulate the daily dose. Obviously, several unit dosage forms can be administered at approximately the same time. The dosage can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose, and adequate much lower maintenance doses may be found. For other patients, prolonged therapy of 1 to 4 doses per day may be necessary, in accordance with the physiological needs of each individual patient. For other patients, it may be necessary to prescribe no more than one or two doses per day.

The compositions can be obtained in unit dosage form by any means well known in the pharmaceutical art. Such methods include the step of binding the pharmaceutically active ingredient to a carrier, which consists of one or more accessory ingredients. Basically, the compositions are obtained by uniform and thorough binding of the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, the product is shaped.

The compositions can be presented in single-dose or multi-dose containers, for example, sealed ampoules and bottles with elastomeric stoppers, and can be stored under freeze-drying (lyophilized), requiring only the addition of a sterile liquid carrier, e.g. water for injection, immediately before use. Injectable solutions and suspensions prepared for immediate administration can be prepared from sterile powders, granules and tablets of the previously described kind.

The pharmaceutical compositions of the present invention preferably comprise a pharmaceutically effective amount of a compound of the present invention. In determining the effective amount or dose, the attending physician considers a number of factors, including, without limitation, the type of mammal; its size, age and general health; the specifics of the disease in question; the degree or complication or severity of the disease; individual patient response; route of administration; characteristics of the bioavailability of the administered drug; selected dosage regimen; the use of concomitant drugs; and other relevant circumstances.

The pharmaceutical compositions of the present invention can be administered with other therapeutic and / or prophylactic agents and / or drugs that are not medically incompatible.

All components of the present compositions should be pharmaceutically acceptable. As used herein, a “pharmaceutically acceptable” component is one which is suitable for use in humans and / or other animals without undue adverse side effects (such as toxicity, irritation, and allergic reaction) corresponding to a reasonable benefit / risk ratio.

The present invention further relates to the use of the pharmaceutical compositions of the present invention in medicine.

2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide is a potent antagonist of the histamine H3 receptor and, in fact , can be used in the treatment of pathologies in which an antagonist of the histamine H3 receptor provides therapeutic benefits. In particular, the compounds of the present invention can be used in the treatment of obesity, diabetes, diseases of the central nervous system, such as insomnia and sleep disorders, narcolepsy, Alzheimer's disease and other dementias, Parkinson’s disease, attention deficit hyperactivity disorder, learning and memory disorders, epilepsy, schizophrenia, mild cognitive impairment, depression, and anxiety. Conditions of depression and anxiety include, for example, anxieties of the expected type (before surgery, before dentistry, etc.), anxiety caused by addiction to alcohol or drugs, or withdrawal symptoms, mania, seasonal affective disorders, migraines and nausea. The compounds of the present invention can also be used in the treatment of sexual dysfunction, dizziness and motion sickness. The compounds of the present invention can also be used in the treatment of cardiovascular disorders and gastrointestinal disorders.

An aspect of the present invention is a method for treating pathologies in which an H3 histamine receptor antagonist provides therapeutic benefit, comprising administering to the patient, if necessary, a pharmaceutically effective amount of a compound selected from the group consisting of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin- 2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate, 2- (cyclo eksilmetil) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide hemifumarate and 2- (cyclohexylmethyl) - N - {2 - [(2 S ) - 1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide hemifumarate dihydrate, or a pharmaceutically effective amount of the pharmaceutical composition of the present invention.

Another aspect of the present invention is a method for treating pathologies in which an H3 histamine receptor agonist provides therapeutic benefits, which comprises administering to the patient, if necessary, a pharmaceutically effective amount of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidine -2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate.

In a specific aspect, the present invention relates to a method for treating a disease of the central nervous system, which comprises administering to the patient, if necessary, said treatment a pharmaceutically effective amount of a compound selected from the group comprising 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1 -methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate hydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl ] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-i l] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide monofumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1, 2,3,4-tetrahydroisoquinolin-7-sulfonamide hemifumarate and 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline -7-sulfonamide hemifumarate dihydrate, or a pharmaceutically effective amount of a pharmaceutical composition of the present invention.

In another specific aspect, the present invention relates to a method for treating the central nervous system, which comprises administering to the patient, if necessary, the indicated treatment a pharmaceutically effective amount of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.

A specific aspect of the present invention is a method for treating a disease or disorder selected from the group consisting of obesity, diabetes, insomnia, sleep disorders, narcolepsy, Alzheimer's disease, dementia, Parkinson's disease, attention deficit hyperactivity disorder, memory disorders, learning disorders, epilepsy, schizophrenia , moderate cognitive disorders, depression, anxiety, sexual dysfunction, dizziness and travel sickness which comprises administering to a patient in need of said treatment f rmatsevticheski effective amount of a compound selected from the group consisting of 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7- sulfonamide difumarate monohydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate, 2- ( cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide monofumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide and 2- hemifumarate (tsiklogeksilm Teal) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate, or a pharmaceutically effective amount of a pharmaceutical composition of the present invention.

Another specific aspect of the present invention is a method of treating Alzheimer's disease, which comprises administering to the patient, if necessary, said treatment a pharmaceutically effective amount of a compound selected from the group comprising 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidine- 2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3, 4 t etrahydroisoquinolin-7-sulfonamide monofumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate and 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate, or a pharmaceutically effective amount of a pharmaceutical composition of the present invention.

Another specific aspect of the present invention is a method of treating Alzheimer's disease, which comprises administering to the patient, if necessary, the indicated treatment a pharmaceutically effective amount of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} - 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.

Another aspect of the present invention is the use of a compound selected from the group consisting of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4- tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate , 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide gemif fumarate and 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate, for the preparation of medicaments for the treatment of pathologies in which the histamine H3 receptor antagonist provides therapeutic benefits.

Another aspect of the present invention is the use of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide monofumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate and 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1- etilpirrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate for the treatment of pathologies in which an antagonist of the histamine H3 receptor provides therapeutic benefit.

Another aspect of the present invention is the use of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate, 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate and 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1- ethylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi-fumarate dihydrate for treating a disease or disorder selected from the group consisting of obesity, diabetes, insomnia, sleep disorders, narcolepsy, Alzheimer's disease, dementia , Parkinson's disease, attention deficit hyperactivity disorder, memory impairment, learning disabilities, epilepsy, schizophrenia, mild cognitive impairment, depression, anxiety , sexual dysfunction, dizziness and motion sickness.

The preparation and properties of the compounds of the present invention are described in the following experimental section. Suitable starting material 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide for the procedures described herein includes, without limitation, 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide obtained by the procedures, described in WO2005 / 118547.

EXAMPLE 1: Preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate

2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide (318 mg, 0.756 mmol) was dissolved in methanol (3 ml). A solution of fumaric acid (29 mg / 3 ml, 2.1 equivalents) was added. The mixture was dried at room temperature in vacuo. The isolated solid was dissolved in isopropanol (1 ml). One milliliter of ethyl acetate was added and the solution was refrigerated. Solids were collected by vacuum filtration.

EXAMPLE 2: Preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate obtained with using the seed stage

2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide (43.7 g, 104 mmol) dissolved in 95% ethanol (200 ml) with heating in a steam bath. Fumaric acid (23.8 g, 203 mmol, 1.95 equivalents) was added, the vessel was washed with 95% ethanol (50 ml). The mixture was heated with rotation to a boil in a steam bath until complete dissolution of fumaric acid. The solution was removed from the steam bath and stirred at room temperature. When the temperature of the solution reached 48 ° C, a seed was introduced which was pre-isolated 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4 Tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate. The mixture was allowed to cool, and at 27.7 ° C it hardened substantially. After settling over the weekend, the mixture was cooled in an ice bath. The solids were collected and washed with ice-cold 95% ethanol (175 ml). After air drying overnight, the lumps were partially broken to give a colorless solid: 58.4 g (84% yield).

The difumarate monohydrate salt was recrystallized from 95% ethanol (350 ml), the previously isolated 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2 was used as a seed , 3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate and stirred until cooling to room temperature. The mixture became very thick, at the end it was so cured that the mixing was practically stopped. After settling at room temperature overnight, the mixture was cooled in an ice bath, and solids were collected by filtration. The filtrate was washed through a filter cake with ice-cold 95% ethanol (50 ml). Then, the filter cake was washed with ice-cold ethanol (125 ml) and dried in air overnight to obtain the desired product as a colorless solid: 49.84 g (72% yield).

EXAMPLE 3: Preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate

2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate (solid, 50 mg) heated at a linear speed of 1.8 ° C / min to 80 ° C at ambient RH and held for 50 minutes to obtain a difumarate salt.

EXAMPLE 4: Preparation of 2- (Cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide anhydride hemifumarate

2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate (17.19 g, 25, 7 mmol) were suspended in approximately 225 ml of water. Potassium carbonate (15.3 g, 111 mmol) was added and the mixture was extracted into ethyl acetate. The organic extract was washed twice with water. Additionally, 5 ml of brine was added to the 2nd wash to break the emulsion. The liquid was concentrated in vacuo. Acetone (approximately 50 ml) was added and the material was concentrated in vacuo. The residue was dissolved in 60 ml of acetone and clarified by filtration to a shine in a vessel (2 × 20 ml washes). A solution of fumaric acid (2.98 g, 25.7 mmol) in 100 ml of acetone and 20 ml of 95% ethanol was added with stirring. The solution became irreversibly cloudy at the end of the addition with a clear oil separation. The material was briefly heated in a steam bath to a boil, then approximately 15 ml of 95% EtOH was added to dissolve the oil. The material was stirred at room temperature overnight. The precipitated solids were filtered and washed with 50 ml of acetone containing 10% ethanol (95%). The filter cake was dried in air for approximately 6 hours under a hood and 4.17 g of 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3 was obtained, 4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate.

After settling in the filtrate, additional crystals formed. The crystals were collected and washed with acetone containing a small amount of 95% ethanol to give 1.08 g of white needles after air drying. The isolated material is 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate.

EXAMPLE 5: Preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemi fumarate dihydrate

The 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide anhydride hemi-fumarate (sludge, solid) was assured mg) at 25 ° C and 60% RH for 2 hours. After 2 hours, the sample was completely converted to hemifumarate dihydrate salt.

EXAMPLE 6: Preparation of 2- (cyclohexylmethyl) - N - {2 - [(2 S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate

Fumaric acid (1.86 g, 16 mmol) was added to 2- (cyclohexylmethyl) - N - {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline- 7-sulfonamide (6.7 g, 16 mmol). DMF (10 ml) and water (500 μl) were added to the mixture, and the solids were dissolved by heating in a steam bath. Isopropyl acetate (30 ml) was gradually added while heating in a steam bath. Heat was removed, and the material was lubricated. The mother liquids were decanted. Approximately 100 ml of MTBE was added to the residual oil, which was stirred for several hours until the mixture became a uniform suspension. The solid was collected and washed with MTBE. The solid was collected and dried by vacuum filtration in a Buchner funnel. NMR showed a ratio of 1.9: 1 fumaric acid to base. The solid was dried in air overnight.

Additional material was crystallized from stock solutions of DMF / isopropyl acetate. After cooling, most of the material was separated as oil. The mixture was reheated to room temperature to redissolve the bulk of the oil. The solids were collected and washed with a small amount of isopropyl acetate. Washing was combined with mother liquids. The solids were air dried overnight. The yield was 0.95 grams.

Most of the material crystallized from the remaining mother liquor. Solids were collected and air was pumped through the filter cake for ½ hour. The yield was 0.7 grams. NMR showed a 1: 1 ratio of fumaric acid to base, meaning monofumarate salt.

The compounds of the present invention were analyzed by the following analytical methods.

Fourier Transform Infrared Spectrometry (FTIR)

IR Fourier spectra were obtained using a Nicolet Magna IR Spectrometer 55 attached to a Nicolet Nic-Plan FT-IR microscope. Data acquisition and parameter settings were controlled using Omnic 7.2 software. Samples were placed on a KBr disk and scanned from 4000 cm ^-1 to 400 cm ^-1 , 32 times. Used a spectral resolution of 4 cm ^-1 .

The FTIR spectrum of the compound obtained generally in Example 2 (see Figure 2) confirmed salt formation and corresponded to the chemical structure of 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl } -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate. Table 1 presents the characteristic wave numbers for 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate . Several intense bands present in the region from 2800 to 2000 cm ^-1 , which are distinguished from the color tone, and combinations of stretching vibrations of the protonated amino group correspond to the formation of an amine salt. The characteristic of stretching vibrations of CO (1650-1550 cm ^-1 ) carboxylate ion can be considered comparable with salts formed from fumaric acid.

Table 1 Wave number characteristics for 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate Wave number
(cm ^-1 +/- 1 ^cm-1) 3436 3243 3049 2930 2851 2656 2587 2504 1698 1647 1634 1580 1449 1332 1302 155 983

Differential Scanning Calorimetry - Thermal Gravimetric Analysis and Mass Spectrometry (DSC-TGA-MS)

Thermal analysis of the compounds of the present invention was performed using TA Model Q-600 instruments of a synchronized differential scanning calorimeter / thermal gravimetric analyzer (DSC-TGA) in a dry helium atmosphere (100 ml / min) attached to a Pfeiffer Quadstar mass spectrometer (DSC-TGA- MS) using a capillary holder at 200 ° C. The temperature of the DSC-TGA was calibrated using reference indium and MS with water vapor. MS determination was performed using a secondary electron multiplier. Powder compounds were transferred to an aluminum tray (inventory number TA 900793.901). A thermogram was achieved at a linear heating rate of 10 ° C per minute.

Thermal analyzes of the difumarate monohydrate salt (Figure 3) show the loss of water (approximately 3.3%) during heating from ambient room temperature to about 100 ° C. The anhydrous phase formed upon loss of water melts at 113-123 ° C under such conditions.

Figure 6 is a combination of thermal (DSC-TGA) profiles of a monofumarate salt with a hemifumarate dihydrate salt and a difumarate monohydrate salt. DSC monofumarate salt shows melting of the crystalline phase at 129 ° C. The melting point of the monofumarate salt is special in comparison with the temperature of the anhydrous difumarate salt (at 113 ° C) and the anhydrous hemifumarate salt (at 137 ° C).

DSC of hemifumarate dihydrate salt showed a wide endothermic effect, concomitant with the release of water, followed by the endothermic effect of melting at 113 ° C (negligible) and 137 ° C (significant). Melting at 137 ° C is unique to the hemifumarate anhydride salt, while a slight endothermic melting effect is associated with the observed melting point of the difumarate anhydride salt.

X-ray Powder Diffractometry (XRPD)

X-ray powder diffractometry carried out on a Siemens-Bruker D5000 diffractometer using Bragg-Brentano parafocus geometry type- (theta-two-theta). The compound of the present invention in the form of a powder is applied to a single crystal silicon wafer cut off according to (510) crystallographic orientation. K-alpha radiation from copper (1.54056 angstroms) emitted from a copper anti-cathode tube (45 kV / 40 mA) is used as an X-ray source, with Cu K-beta radiation filtered using a monochromator with a reflected beam. A scintillation counter is used to determine. We used a divergence slit of 0.6 mm, an anti-scattering slit of 0.6 mm, a monochromator slit of 0.1 mm, and a detector slit of 0.6 mm. A diffraction pattern is obtained using the following conditions: at least 2.0-30.0 degrees of scanning at a 2-theta angle, counting time per step of 1.0 second, step size 0.02 degrees under ambient conditions of pressure, temperature and relative humidity except as agreed. Temperatures above ambient were achieved by heating the sample at a linear speed of 0.03 to 0.06 ° C / second.

The XRPD spectrum (Figure 1) confirmed that 2- (cyclohexylmethyl) - N - {2 - [(2 S ) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide difumarate monohydrate was crystalline.

Based on the XRPD spectra, the crystalline difumarate anhydride salt (Figure 4) has a characteristic XRPD spectrum compared to the crystalline difumarate monohydrate salt.

Figure 5 shows the XRPD spectrum of a crystalline monofumarate salt. The data show that the crystal structure of the monofumarate salt is special compared to the crystalline structures of difumarate, difumarate monohydrate, hemifumarate and hemifumarate dihydrate salts.

The figure 7 shows the overlap of the XRPD spectra of salts of crystalline hemifumarate and crystalline hemifumarate dihydrate. The XRPD spectrum of the hemifumarate dihydrate salt and the corresponding hemifumarate anhydride salt differs significantly from the salts of diphumarate monohydrate, diphumarate anhydride and monofumarate.

One skilled in the art will recognize that peak positions may be slightly affected by differences in sample height. The peak positions described herein are thus subject to a plus or minus (+/-) 0.15 degree 2-theta change. The relative intensities may vary depending on the size and morphology of the crystal.

Table 2 summarizes the characteristic peak positions, d-scatter, and relative intensities for the powder X-ray diffraction pattern for the difumarate monohydrate salt.

table 2
Characteristic positions of XRPD peaks and relative intensities of the difumarate monohydrate salt Degrees of the measured angle 2θ
+/- 0.15º 2θ The value of the calculated spread d
(angstroms) Relative intensity
(%) 5.31 16.62 7.1 5.84 15.12 69.6 7.00 12.62 27.4 8.67 10.19 11.3 11.71 7.55 6.5 13,99 6.33 8.3 17.17 5.16 13.1 17.59 5.04 20.8 18.45 4.81 one hundred 19.32 4,59 13.1 21.05 4.22 15,5 21.69 4.09 25.0

In particular, peaks at 5.31, 5.84, 7.00 and 8.67 (expressed in degrees 2-theta +/- 0.15 degrees) are characteristic of the difumarate monohydrate salt.

Table 3 summarizes the characteristic peak positions, d-scatter, and relative intensities for the X-ray powder diffraction pattern for the difumarate salt.

Table 3
Characteristic positions of XRPD peaks and relative intensities of the difumarate salt Degrees of the measured angle 2θ
+/- 0.15º 2θ The value of the calculated spread d
(angstroms) Relative intensity
(%) 5.21 16.94 17.6 5.67 15,57 38.3 7.06 12.51 24.3 11.34 7.79 36.0 11.70 7.56 26.6 13.24 6.68 9.0 14.17 6.25 7.7 17.01 5.21 67.1 17.46 5.08 35.6 17.80 4.98 26.6 18.54 4.78 one hundred 20.87 4.25 52.3 21.36 4.16 51,4 22.75 3.90 59.9 23.68 3.76 14.9 24.15 3.68 20.3 25.53 3.49 24.3

In particular, peaks at 5.21, 5.67, 7.06, and 11.34 (expressed in degrees 2-theta +/- 0.15 degrees 2-theta) are characteristic of the difumarate salt.

Table 4 summarizes the characteristic peak positions, d-scatter, and relative intensities for a powder X-ray diffraction pattern for a monofumarate salt.

Table 4
Characteristic positions of XRPD peaks and relative intensities of monofumarate salt Degrees of the measured angle 2θ
+/- 0.15º 2θ The value of the calculated spread d
(angstroms) Relative intensity
(%) 3.37 26.24 33.9 6.70 13.19 13,2 13.36 6.62 11.1 14.83 5.97 22.4 15.88 5.58 29.9 17.65 5.02 one hundred 18.16 4.88 34.5 18.84 4.71 18,4 19.45 4,56 18,4 19.87 4.46 35.6 21.52 4.13 35.1 22.09 4.02 37,4 22.52 3.95 29.9 23.06 3.85 51.7 24.42 3.64 15,5 25.81 3.45 13.8

In particular, peaks at 3.37, 6.70, 13.36, 14.83, 15.88 and 17.65 (expressed in degrees 2-theta +/- 0.15 degrees 2-theta) are characteristic of monofumarate salt .

Table 5 summarizes the characteristic peak positions, d-scatter, and relative intensities for a powder X-ray diffraction pattern for a hemifumarate salt.

Table 5
Characteristic positions of XRPD peaks and relative intensities of hemifumarate salt Degrees of the measured angle 2θ
+/- 0.15º 2θ The value of the calculated spread d
(angstroms) Relative intensity
(%) 3.61 24.48 3.9 7.22 12.24 2,3 7.96 11.10 4,5 8.21 10.76 7.3 9.01 9.80 2,3 10.82 8.17 3.9 11.93 7.41 1.8 12.60 7.02 2.2 14.10 6.28 2,5 14.82 5.97 2,3 15.66 5.66 one hundred 16.19 5.47 9.1 16.47 5.38 40.7

In particular, peaks at 3.61, 7.22, 7.96, 8.21, 9.01, 10.82 and 15.66 (expressed in degrees 2-theta +/- 0.15 degrees 2-theta) are a characteristic of hemifumarate salt.

Table 6 summarizes the characteristic peak positions, d-scatter, and relative intensities for a powder X-ray diffraction pattern for a hemifumarate dihydrate salt.

Table 6
Characteristic positions of XRPD peaks and relative intensities of hemifumarate dihydrate salt Degrees of the measured angle 2θ
+/- 0.15 ° 2θ The value of the calculated spread d
(angstroms) Relative intensity
(%) 3.49 25.29 4,5 6.93 12.75 2.7 8.46 10.45 12.1 10.34 8.55 4.0 13.25 6.68 1.9 13.75 6.43 2,4 15.40 5.75 100.0 15.77 5.61 4.6 16.61 5.33 7.2 16.86 5.25 14.3 17.21 5.15 10.3 17.84 4.97 5,0 18,20 4.87 7.4 18.55 4.78 4.7 18.86 4.70 6.7 19.11 4.64 5.7 19.75 4.49 9,4 20.07 4.42 7.0

In particular, peaks at 3.49, 6.93, 8.46, 10.34, 13.25, 13.75 and 15.40 (expressed in degrees 2-theta +/- 0.15 degrees 2-theta) are a characteristic of hemifumarate dihydrate salt.

Dynamic vapor sorption

The water sorption profile of the compounds of the present invention is determined using SMS tools of the dynamic vapor sorption analyzer (DVS) model DVS-Advantage. Relative humidity (RH) and weight are calibrated using standards. The powder of the relevant compound of the present invention is loaded and dried at 0% RH for 3 hours before the start of the experiment. RH changes in stages from 0.1 to 94.4% in 11 stages. The weight of the sample is considered constant at each stage if the percentage change in mass is less than 0.01% for a 5-minute interval with a minimum absolute equilibrium time of 15 minutes and a maximum equilibrium time of 180 minutes.

Figure 8 is a DVS profile of the difumarate monohydrate salt and the corresponding difumarate salt, and the numerical data are presented in Table 7. The profile shows that the difumarate monohydrate salt is stable at RH from 10% to 94% at 25 ° C.

Table 7
Digital DVS data for the difumarate monohydrate salt and the corresponding difumarate salt Sample (% RH) Mass change (%) upon drying Sorption Desorption 0.6 0,0 0,0 10,2 2,8 2.9 19.6 2.9 2.9 29.4 3.0 3.0 38.5 3.0 3.0 48.5 3.0 3.0 57.5 3,1 3,1 67.1 3,1 3,1 77.0 3,1 3.2 87.0 3.2 3.2 94.2 3.3 3.3

Figure 9 is a DVS profile of the hemifumarate dihydrate and corresponding hemifumarate salts, and the numerical data are presented in Table 8. The profile shows that the hemifumarate monohydrate salt is stable at RH from 19% to 92% at 25 ° C.

Table 8
DVS Digital Data for Hemifumarate Dihydrate and Related Hemifumorate Salt Sample (% RH) Mass change (%) upon drying Sorption Desorption 0.6 0.00 0.00 10.1 0.25 0.56 19,4 3.53 6.71 29.0 3.87 6.85 37.8 6.50 6.89 47.7 6.89 6.97 56.4 7.01 7.10 65.7 7.13 7.21 75.3 7.32 7.33 84.8 7.68 7.66 92.0 8.31 8.25

Stability testing

1. Storage at 60 ° C and ambient RH for two weeks

Approximately 400 mg of the difumarate monohydrate salt was weighed in a scintillation vial and placed in an oven set at 60 ° C. The sample was tested in appearance, then diluted with ethanol to approximately 1 mg / ml and analyzed for related substances and the optical enantiomer by HPLC.

After storage at 60 ° C for 14 days, the difumarate monohydrate salt did not show a visible change in physical form using XRPD and DSC-TGA. Difumarate monohydrate appears to be physically stable under these storage conditions. Regarding chemical stability, the difumarate monohydrate salt is apparently stable in the solid state with a minimal increase in impurity levels, and there is no visible change in appearance.

2. Storage at 60 ° C / 80% RH and ambient RH for two weeks

The glass dehydration chamber was pre-equilibrated overnight with a saturated KBr solution to 79.3% RH in an 80 ° C oven. Approximately 400 mg of difumarate monohydrate was weighed in a scintillation vial and placed in a chamber, which was then sealed to preserve the environment. Samples were tested in appearance, then diluted with ethanol to approximately 1 mg / ml and analyzed for related substances and the optical enantiomer by HPLC.

After storage at 60 ° C / 80% RH for 14 days, the difumarate monohydrate salt did not show a visible change in physical form using XRPD and DSC-TGA. The difumarate monohydrate salt is apparently physically stable under these storage conditions. Regarding chemical stability, the difumarate monohydrate salt is apparently stable in the solid state with a minimal increase in impurity levels, and there is no visible change in appearance.

3. Storage at 80 ° C / 80% RH for 4 days

The glass dehydration chamber was pre-equilibrated overnight with a saturated KBr solution to 79.3% RH in an 80 ° C oven. Approximately 100 mg of the difumarate monohydrate salt was weighed in appropriate scintillation vials, and these vials were placed in a chamber, which was then sealed to preserve the environment. On day 4, the sample was tested in appearance, then diluted with ethanol to approximately 1 mg / ml and analyzed by HPLC relative to the control sample (time 0).

After storage at 80 ° C / 80% RH for 4 days, the difumarate monohydrate salt was stable in the solid state without visible chemical changes.

Claims (16)

1. The compound selected from the group including
2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate;
2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate;
2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide monofumarate;
2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate and
2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide hemifumarate dihydrate. 2. A pharmaceutical composition having the properties of an antagonist of the histamine H3 receptor, containing the compound according to claim 1 and a pharmaceutically acceptable carrier. 3. A pharmaceutical composition having the properties of an histamine H3 receptor antagonist obtained by formulating the compound of claim 1 with one or more pharmaceutically acceptable carriers. 4. A method of obtaining a pharmaceutical composition comprising formulating a compound according to claim 1 with one or more pharmaceutically acceptable diluents. 5. The compound according to claim 1, which is 2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate monohydrate. 6. The compound according to claim 5 in crystalline form. 7. A pharmaceutical composition having the properties of an antagonist of the histamine H3 receptor, containing the compound according to claim 5 and a pharmaceutically acceptable carrier. 8. A pharmaceutical composition having the properties of an antagonist of the histamine H3 receptor, obtained by formulating the compound according to claim 5 with one or more pharmaceutically acceptable carriers. 9. A method of obtaining a pharmaceutical composition comprising formulating a compound according to claim 5 with one or more pharmaceutically acceptable diluents. 10. The compound according to claim 1, which is 2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinoline-7-sulfonamide difumarate in crystalline form. 11. The compound according to claim 1, which is 2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide monofumarate in crystalline form. 12. The compound according to claim 1, which is 2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide hemifumarate in crystalline form. 13. The compound according to claim 1, which is 2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-sulfonamide hemi-fumarate dihydrate in crystalline form. 14. The method of obtaining 2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4-tetrahydroisoquinolin-7-
sulfonamide difumarate monohydrate, comprising the steps of contacting at elevated temperature or at ambient temperature 2- (cyclohexylmethyl) -N- {2 - [(2S) -1-methylpyrrolidin-2-yl] ethyl} -1,2,3,4- tetrahydroisoquinoline-7-sulfonamide, dissolved in a suitable solvent or mixture of solvents, with fumaric acid, optionally dissolved in a solvent or in a mixture of solvents; and the selection of precipitated solids. 15. The use of a compound according to claim 1 for the treatment of a disease or disorder selected from the group consisting of obesity, diabetes, insomnia, sleep disorders, narcolepsy, Alzheimer's disease, dementia, Parkinson's disease, attention deficit hyperactivity disorder, memory disorders, learning disorders, epilepsy, schizophrenia, mild cognitive impairment, depression, anxiety, sexual dysfunction, dizziness and motion sickness. 16. A method for treating a disease or disorder selected from the group consisting of obesity, diabetes, insomnia, sleep disorders, narcolepsy, Alzheimer's disease, dementia, Parkinson's disease, attention deficit hyperactivity disorder, memory disorders, learning disorders, epilepsy, schizophrenia, mild cognitive disorders, depression, anxiety, sexual dysfunction, dizziness and motion sickness, comprising administering to a patient in need of said treatment a pharmaceutically effective amount of a compound according to claim 1.

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